Abstract 224: Methyl-CpG-binding domain protein 2 (Mbd2) as a therapeutic target in breast cancer

Abstract Abnormal DNA methylation is frequently observed in the cancer epigenome, rendering it a prime target for pharmacological manipulation. Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been shown to be strongly linked to various malignancies, including breast cancer, establishing Mbd2 as a viable and effective therapeutic target. Our previous studies have demonstrated that genetic deletion of Mbd2 significantly reduces primary breast tumor growth and lung metastasis in a well-established transgenic mouse model of breast cancer. In the current study, we examined the effect of pharmacological inhibition of Mbd2 on breast cancer progression and metastasis to non skeletal and skeletal sites. Several small-molecule inhibitors for Mbd2 have been described, and among these, KCC-07 was shown to significantly reduce medulloblastoma in vitro and in vivo. Treatment of mouse luminal B breast cancer cell lines (PyMT-R221A, E0071) with KCC-07 resulted in a time- and dose-dependent decrease in tumor cell proliferation and reduced the invasiveness of the cells in vitro. These results were recapitulated in vivo, where PyMT-R221A cells inoculated via mammary fat pad (m.f.p) and intra-tibial (i.t) routes into female FVB mice and treated with vehicle alone or KCC-07 (100.0 mg/kg) 3QW via the intraperitoneal route for three weeks showed a decrease in tumor volume and skeletal metastasis. Further immunohistochemical analyses of the tumor tissues using markers of tumor proliferation (Ki67), angiogenesis (CD31), and bone resorption (TRAP), as well as any potential side effects on animal toxicity and global transcriptomic changes of the PyMT-R221A cells induced by treatment with KCC-07, will be presented and discussed. In other studies, PyMT-R221A cells were treated with the most effective dose of Mbd2 siRNA and KCC-07 (40µM) and cellular RNA from control and experimental groups was extracted and subjected to RNA-seq analysis, which is now being analyzed and validated in depth. Results from these analyses will identify key Mbd2-mediated signaling pathways and genes that play an important role in breast cancer. Taken together, the results of this study will provide mechanistic insights into the therapeutic potential of targeting Mbd2 with KCC-07 to block breast cancer growth and metastasis in a preclinical setting. These findings could be highly valuable for the future evaluation of selective inhibitors of Mbd2 to treat breast cancer patients. Citation Format: Olivia Dumas, Niaz Mahmood, Ani Arakelian, Moshe Szyf, Shafaat Rabbani. Methyl-CpG-binding domain protein 2 (Mbd2) as a therapeutic target in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 224.